Causes of Sinusoidal Obstruction Syndrome (SOS)
Sinusoidal obstruction syndrome is primarily caused by three major categories: hematopoietic stem cell transplantation (HSCT) conditioning regimens, chemotherapeutic agents (particularly oxaliplatin), and pyrrolizidine alkaloid-containing herbal remedies, with numerous other drugs and toxins also implicated. 1
Primary Etiologic Categories
1. Hematopoietic Stem Cell Transplantation (HSCT)
The most well-established cause of SOS is myeloablative conditioning regimens used before HSCT. This represents the classic setting where SOS was first extensively characterized, though incidence has declined from 50% historically to approximately 14% currently due to improved prophylaxis and modified conditioning protocols 1.
2. Chemotherapeutic Agents
Specific drugs associated with SOS include:
- Alkylating agents: Cyclophosphamide, busulfan, melphalan, carmustine
- Antimetabolites: Cytosine arabinoside, mercaptopurine, 6-mercaptopurine, 6-thioguanine
- Antibiotics: Actinomycin D, mitomycin
- Targeted therapy: Gemtuzumab-ozogamicin
- Platinum-based: Oxaliplatin (particularly in colorectal liver metastasis treatment)
- Other agents: Dacarbazine, urethane 1
Oxaliplatin deserves special mention as it causes SOS in the context of neoadjuvant/adjuvant treatment for colorectal liver metastases, leading to increased operative bleeding, post-operative liver dysfunction, and delayed liver regeneration 1.
3. Pyrrolizidine Alkaloids (PAs)
Traditional herbal remedies containing PAs are an increasingly recognized cause, particularly in Eastern populations. Specific herbs include:
This etiology is particularly important as it represents a preventable cause through public awareness and regulatory oversight 4, 3.
4. Immunosuppressive Agents
- Azathioprine (used in solid organ transplantation and inflammatory bowel disease)
- Terbinafine 1
5. Radiation Therapy
- Total body irradiation
- High-dose hepatic irradiation 1
6. Other Causes
- Platelet transfusion containing ABO-incompatible plasma 1
- Immune checkpoint inhibitors (extremely rare but increasingly reported) 5
- Intravesical mitomycin-C (rare, particularly with traumatic catheterization causing systemic absorption) 6
Pathophysiologic Mechanism
Regardless of the causative agent, SOS follows a common pathway: initial injury to sinusoidal endothelial cells leads to endothelium denudation, cell embolization toward central hepatic zones, and subsequent sinusoidal obstruction with outflow block. This can progress to centrilobular hepatocellular necrosis, perisinusoidal fibrosis, and nodular regenerative hyperplasia 1, 7.
Clinical Pitfalls
Critical considerations:
- Delayed presentation: SOS can manifest months to years after exposure (e.g., azathioprine, 6-thioguanine, toxic oil syndrome showed portal hypertension 2.5 years post-exposure) 1
- Context-dependent timing: In HSCT with cyclophosphamide, onset typically occurs within 20 days; other regimens may present later 1
- Persistent lesions: Even after stopping oxaliplatin, histological changes and portal hypertension may persist for 1-3 years 1
- Misdiagnosis risk: Non-specific presentation can lead to misdiagnosis as other liver diseases, particularly in PA-induced cases 2
Risk Factor Recognition
Key risk factors that increase SOS susceptibility:
- Pre-existing liver disease or cirrhosis
- Previous SOS episode
- Type and intensity of conditioning/chemotherapy regimen
- Female gender (in solid cancer treatment)
- Elevated baseline gamma-glutamyl transpeptidase
- Genetic polymorphisms (glutathione S-transferase gene) 1
The critical clinical message: Always maintain high suspicion for SOS in any patient with hepatomegaly, ascites, and jaundice following HSCT, chemotherapy, immunosuppression, or herbal remedy ingestion, as this condition carries significant morbidity and mortality that can approach 100% in severe cases. 1